Nitroxyl (HNO) is a novel nitrogen oxide species with unique and important biological activity. One of its most provocative and therapeutically novel attributes is its potential for the treatment of heart failure. HNO possesses an almost perfect combination of biological activities for this purpose. The proposal The Biological Chemistry and Pharmacology of Nitroxyl (HNO) intends to develop a series of HNO- donor molecules for use as potential drug candidates as well as research tools. The actions of these molecules will be examined in in vitro systems to assess their potential as pharmacological agents. Further, we intend to assess possible mechanisms by which HNO acts. More specifically, we will assess the relationship between the signaling molecule hydrogen peroxide (H2O2) and HNO. The rationale for this is based on the near identical biochemical targets for HNO and H2O2, their related and overlapping biological activities and the likelihood that HNO can dramatically alter H2O2 metabolism. In all, this proposal serves to 1) develop novel and important HNO donors for use in the laboratory and, eventually, to serve as the basis for possible drug development and 2) examine their activity as vascular agents and the possible role of H2O2 in this regard. PUBLIC HEALTH RELEVANCE: Heart failure is a leading cause of hospitalization of people over 65 in the United States. Over 5 million people have been diagnosed with heart failure and over 300,000 people die annually in the US. Currently, the treatments for heart failure are relatively ineffective making development of other treatments an important objective. By all accounts, nitroxyl (HNO) possesses a near perfect spectrum of activity for the treatment of heart failure and is mechanistically unrelated to most other drugs. Moreover, HNO has been proposed to be useful for preventing ischemia-reperfusion injury and even for the treatment of alcoholism. This proposal intends to synthesize HNO donors for use as possible drugs and/or research tools. Also, the mechanism of HNO activity will be examined and its relationship with other important signaling systems established.